tbuckley/cabot-search huggingface dataset:
Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction (PCR) versus next-generation sequencing (NGS) testing strategies in metastatic non-small cell lung cancer (mNSCLC).
Authors: Christine M. Bestvina, Dexter Waters, Laura Morrison, Bruno Emond, Marie-Hélène Lafeuille, Annalise Hilts, Patrick Lefebvre, Andy He, Julie Vanderpoel
Journal: Journal of Clinical Oncology (2023)

6638 Background: NGS testing for genomic alterations has been found to expedite time to appropriate targeted therapy initiation compared to PCR testing in mNSCLC. This study assessed US payers’ costs of testing, delayed care, and suboptimal treatment initiation for PCR versus NGS testing in patients with mNSCLC. Methods: A decision tree model evaluated testing for guideline-recommended alterations (EGFR, ALK, ROS1, BRAF, KRAS, MET, HER2, RET, NTRK1/2/3) in patients with newly-diagnosed mNSCLC from first test until appropriate therapy initiation using 1) liquid or tissue NGS (60% [90% tissue, 10% liquid] of patients), 2) exclusionary KRAS test followed by sequential PCR tests (5%), 3) sequential PCR tests (5%), or 4) hotspot panel (30%) PCR tests. The proportion of patients testing positive for a targetable alteration and time to appropriate therapy initiation were evaluated. Cost components included genetic testing, testing-related medical services, delayed care (i.e., costs for medical services while waiting for test results), immunotherapy [IO]/chemotherapy [CTX] initiation prior to test results, and suboptimal treatment initiation after test results (i.e., costs of first-line IO/CTX in patients falsely testing negative for an actionable mutation). Results: In a modeled cohort of 1 million members (75% commercial, 25% Medicare), an estimated 1,119 patients had mNSCLC and were tested. The proportion of patients testing positive for a targetable alteration was 45.9% for NGS and 39.4% for PCR testing (Table). Total mean per patient costs were lower for NGS ($8,866) than for PCR ($18,252), driven by more rapid treatment with appropriate therapy (2.1 versus 5.2 weeks), resulting in lower delayed care costs and IO/CTX costs prior to test results. Conclusions: Results suggest that NGS testing may lead to better patient care and reduced costs to the health system relative to PCR testing. Costs of inappropriate IO/CTX initiation are an important component of increased costs of PCR-based approaches. [Table: see text]
Intrathecal anti-PD-1 treatment in patients with metastatic melanoma (MM) with leptomeningeal disease (LMD): Real-world data and evidence.
Authors: Junjie Zhen, Xiaoshi Zhang, Linbo Cai, Linbin Chen, Mingyao Lai, Dandan Li, Hui Wang, Ya Ding, Yanying Yang, Jingjing Li, Xizhi Wen
Journal: Journal of Clinical Oncology (2023)

e21516 Background: LMD is one of the most severe complications of melanoma and has an extremely poor prognosis. Over the past decade, the incidence of LMD is increasing with improved treatment strategies and prolonged survival. This real-world study aims to evaluate the safety and efficacy of intrathecal anti-PD-1 treatment in MM patients with LMD. Methods: MM patients with LMD diagnosed by MRI and/or cerebrospinal fluid (CSF) cytology were assigned to intrathecal nivolumab infusion 20mg once every 2 weeks (n = 4) or pembrolizumab 20mg once every 3 weeks (n = 3). The patients received a median of 4 cycles of treatment (range 2–7 cycles). Efficacy and safety analyses were performed on all the treated patients. Results: Between June 2022 and December 2022, 7 patients were treated, including 3 cutaneous, 2 acral and 2 primary leptomeningeal melanoma. All patients presented linear or small nodular enhancement of leptomeningeal on MRI. Four patients had concurrent parenchymal brain metastases. The tumor cells were found in 5 patients by CSF cytology, and pathologic diagnosis was obtained by leptomeningeal biopsy in 2 patients. According to RANO-LM criteria, 4 patients responded to treatment with symptom improvement and reduction or disappearance of linear enhancement on MRI, while 3 patients developed progressive disease. The median overall survival (OS) was 39.7 months after initial diagnosis and 24 weeks after LMD. With a median follow-up of 13.3 weeks (range 9.4–20.3 weeks), the median intracranial progression-free survival (IPFS) and median OS for intrathecal anti-PD-1 were 16.1 and 20.3 weeks, respectively. All treatment-related adverse events were grade 1-2, including headache (grade 1, n = 1; grade 2, n = 2) and low back pain (grade 1, n = 1). Conclusions: In this real-world study, intrathecal anti-PD-1 treatment was found to be well tolerated and effective in metastatic melanoma patients with LMD.
Efficacy and safety of encorafenib (enco) plus binimetinib (bini) in patients with <i>BRAF</i> V600E-mutant (<i>BRAF</i><sup>V600E</sup>) metastatic non-small cell lung cancer (NSCLC) from the phase 2 PHAROS study.
Authors: Gregory J. Riely, Egbert F. Smit, Myung-Ju Ahn, Enriqueta Felip, Suresh S. Ramalingam, Anne S. Tsao, Melissa Lynne Johnson, Francesco Gelsomino, Raymond M. Esper, Ernest Nadal, Michael Offin, Mariano Provencio-Pulla, Gregory Alan Otterson, Ibiayi Dagogo-Jack, Ann Alcasid, Tiziana Usari, Keith D. Wilner, Nuzhat Pathan, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2023)

9018 Background: The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, is a current standard of care for patients (pts) with BRAF V600E NSCLC. We report efficacy and safety of enco+bini in pts with BRAF V600E metastatic NSCLC. Methods: PHAROS is an ongoing, open-label, single-arm, phase 2 study that enrolled pts with BRAF V600E metastatic NSCLC who had measurable disease by RECIST 1.1 and Eastern Cooperative Oncology Group performance status of 0 or 1, and who were either treatment-naive or had received 1 prior therapy (chemotherapy, monotherapy, or combination immunotherapy) for metastatic disease. Exclusion criteria included prior treatment with a BRAF or MEK inhibitor. Pts received enco 450 mg QD + bini 45 mg BID administered orally in 28-day cycles. The primary endpoint was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and time to response (TTR), all by IRR, and safety. Exploratory endpoints included biomarker assessments. Results: At the data cutoff (Sep 22, 2022), 98 pts (59 treatment-naive, 39 previously treated) received enco+bini. The median duration of treatment was 9.2 months with enco and 8.4 months with bini. Treatment is ongoing in 34% of the pts; 38% permanently discontinued due to disease progression and 18% due to adverse events (AEs). The ORR (95% CI) by IRR was 75% (62, 85) in treatment-naive and 46% (30, 63) in previously treated pts. Secondary endpoints are shown in the table. The most frequent (≥30%) treatment-related AEs (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). AEs led to permanent discontinuation of enco+bini in 15% of pts and dose reductions in 24% of pts. One grade 5 TRAE of intracranial hemorrhage was reported. Next-generation sequencing analysis was conducted with archival tumor biopsies from 48 treatment-naive and 32 previously treated pts. The most frequent genomic alterations, in addition to BRAF V600E , were SETD2 and TP53 (43% each), SMAD4 (21%), ATM, MLL2, CSF1R, and SMARCA4 (14% each), and CDKN2A (11%). Conclusions: The combination of enco+bini showed meaningful clinical benefit in treatment-naive and previously treated pts with BRAF V600E metastatic NSCLC. The safety profile of enco+bini was generally consistent with that established for pts with BRAF V600E/K melanoma. ClinicalTrials.gov: NCT03915951. Clinical trial information: NCT03915951 . [Table: see text]
IMRT followed by pembrolizumab in the adjuvant setting in anaplastic cancer of the thyroid (IMPAACT): Phase II trial adjuvant pembrolizumab after IMRT in ATC.
Authors: Maria E. Cabanillas, Gary Brandon Gunn, Mark E. Zafereo, Rui Jennifer Wang, Priyanka C. Iyer, Anastasios Maniakas, Michael T Spiotto, Ramona Dadu
Journal: Journal of Clinical Oncology (2023)

TPS6117 Background: Anaplastic thyroid carcinoma (ATC) has historically been an almost uniformly rapidly fatal disease. In patients with loco-regional disease with no distant metastasis (stage IVB), and without a targetable mutation, a combination of external beam radiation delivered via intensity modulated techniques (IMRT) +/- concurrent cytotoxic chemotherapy is the current standard of care. However, the relapse rate is very high within the first year of diagnosis. Our data show that 90% of ATCs express PD-L1, with 43% having expression levels greater than 50%. A clinical trial with an anti-PD1 drug in ATC patients with active disease showed that patients with ATC had a response rate of 19%. Additionally, as tumor PD-L1 expression has been linked to radioresistance and there is a need to target micrometastatic disease, using adjuvant checkpoint inhibitor is a rational strategy in these patients. Methods: This is an open label, single center, phase 2 trial of adjuvant pembrolizumab after external beam radiation to the primary tumor in patients with stage IVB ATC. The primary cohorts will include those with gross, locoregional disease who have completed treatment with IMRT +/- concurrent radiosensitizing chemotherapy. Patients will be treated with adjuvant pembrolizumab (400mg IV Q6 weeks for up to 9 cycles), 2-6 weeks after completion of radiation. Patients will be enrolled based on dose of radiation in cohort 1 (high dose group, &gt; 51 Gy), cohort 2 (palliative dose group, &lt; 50 Gy). Cohort 3, consisting of those who underwent surgery followed by IMRT plus concurrent chemotherapy will be an exploratory cohort. Restaging scans will be performed every 12 weeks after enrollment. MRI brain will be repeated every 6 months in the absence of evidence of progression. The primary endpoint is median PFS (from the start of adjuvant pembrolizumab) in cohorts 1 and 2. Secondary endpoint is median overall survival in cohorts 1 and 2. Cohort 3 (5 patients) will have an exploratory endpoint, to estimate the median disease-free survival (DFS). Statistics: Survival analyses will be performed using the Kaplan-Meier method. Based on historical data, the median PFS for unresected patients is 6.8 months. For an expected improvement of median PFS by 3.7 months, with a combined total of 30 evaluable patients in cohorts 1 and 2, we anticipate having 80.0% power using 1-sided 10% alpha for a one-sample log rank test. The trial began enrollment in July 2022. This trial is sponsored by philanthropic funds and Merck. ClinicalTrials.gov ID NCT05059470. Clinical trial information: NCT05059470 .
The impact of circulating tumor cell HOXB13 RNA detection in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide.
Authors: Siyuan S Guo, Susan Halabi, David M. Nanus, Daniel J. George, Emmanuel S. Antonarakis, Daniel Costin Danila, Russell Zelig Szmulewitz, Donald P. McDonnell, John D. Norris, Changxue Lu, Jun Luo, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2023)

5060 Background: It has been shown that HOXB13 is an important androgen receptor (AR) coregulator. The primary objective of this analysis was to correlate HOXB13 expression with clinical outcomes in men with mCRPC. Methods: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (n=118) treated abiraterone (abi) or enzalutamide (enza). CTC detection and specific HOXB13 cDNA detection and expression was measured using a modified Adnatest using appropriate controls. CTC HOXB13 status was categorized into 3 groups: undetectable CTCs (CTC=0 based on CTC PSMA &amp; PSA=0); CTC+ but HOXB13 CTC negative (&lt;4 copies) or positive (≥4 copies) where the HOXB13 cutoff point was determined by the maximally selected rank statistic for prognostic associations. The association between HOXB13 and overall survival (OS) and radiographic progression-free survival (rPFS) were explored using the proportional hazards model. We also explored the association between the two endpoints and multigroup of HOXB13 at cutoff 0 and CellSearch CTC at cutoff 1 and 5. Results: 102 men who had sufficient CTC cDNA sample for HOXB13 detection. Of those men with detectable CTCs, 19% (n=19) had no detectable HOXB13, while the majority of men at 67% (n=58) had both CTC and HOXB13 detection. The proportion of patients with CTC=0, CTC+ HOXB13-, and CTC+ HOXB13+ using the optimal HOXB13 threshold were 25%, 31% and 44%, respectively. Men with HOXB13- CTCs were more likely to have low PSA (median 3 vs 79 copies), low CTC PSMA (0 vs 99 copies), low AR-FL (47 vs. 89 copies) and CTC AR-V7 (5.9 vs. 42 copies), and more likely to have liver/lung metastases (41% vs 25%). Median OS were 25.7, 25 and 12.1 months while the median rPFS of the three groups were 9.0, 7.2 and 4.7 months, respectively. Compared to CTC=0, men with HOXB13- CTCs did not have a worse hazard rate for OS (HR: 0.9, 95% CI: 0.4-1.9), while HOXB13+ CTC patients had a worse hazard for OS (HR: 2.0, 95% CI: 1.0-3.9), adjusting for prior abi/enza treatment and Halabi clinical risk score. The positive HOXB13 had also statistically significant increased hazard for progression/death (HR: 2.31, 95% CI: 1.24-4.30). Compared to the group with both HOXB13=0 and CellSearch CTC=0, men with HOXB13&gt;0 and CellSearch CTC≥5 had increased hazard on both OS and rPFS (OS: HR:2.39, 95% CI: 1.06-5.4; rPFS: HR: 2.78, 95% CI: 1.38-5.59). Conclusions: Higher CTC HOXB13 expression is associated with AR dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC, and this assay could be useful to select for patients appropriate for AR or future HOXB13 targeted therapies. Clinical trial information: NCT02269982 .
Inotuzumab ozogamicin (INO) for the treatment of measurable residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL): Results from a phase II study.
Authors: Lewis Fady Nasr, Nicholas James Short, Jayastu Senapati, Yesid Alvarado Valero, Nitin Jain, Marina Konopleva, Walid Macaron, Farhad Ravandi, Courtney Denton Dinardo, Koji Sasaki, Alessandra Ferrajoli, Cedric Christophe Nasnas, Marianne Zoghbi, Jovitta Jacob, Ejiroghene Mayor, Anna Milton, Christopher Loiselle, Rebecca Garris, Hagop M. Kantarjian, Elias Jabbour
Journal: Journal of Clinical Oncology (2023)

e19008 Background: INO is effective in relapsed/refractory B-ALL and may have utility in eradicating MRD in patients (pts) in MRD-positive (MRD+ve) remission. Methods: This is a phase II trial of pts with B-ALL in complete remission (CR) with persistent MRD+ve or with MRD+ve relapse. Eligible pts were required to be MRD+ve at ≥0.01%. MRD negativity (MRD-ve) was defined as undetectable MRD by flow cytometry (sensitivity 10 -4 ) for Philadelphia (Ph)-negative (Ph-) B-ALL and undetectable MRD by both flow and PCR for BCR:ABL1 for Ph-positive (Ph+) B-ALL. INO was given at a dose of 0.6 mg/m 2 on D1 and 0.3 mg/m 2 on D8 of cycle 1 and 0.3 mg/m 2 on D1 and 8 of subsequent cycles (up to 6 total cycles, given every 21-28 days) along with ursodiol prophylaxis. Pts with Ph+ ALL received concomitant TKI. Results: 27 pts with MRD+ve B-ALL were treated between 11/2018 and 6/2022 (Table). 17 pts (63%) had Ph+ B-ALL (15 received ponatinib and 2 dasatinib), and 10 pts had Ph- B-ALL. 20 pts (74%) were in CR1, and 7 pts (26%) were in CR2 or beyond. 14 pts (52%) had received prior blinatumomab and 5 pts (18%) had prior stem cell transplantation (SCT). 18 pts (67%) became MRD-ve (responders), 16 after the 1st cycle and 2 after the 2nd cycle of INO. In the Ph+ group, 10/17 pts (59%) responded; another 3 pts achieved major molecular response. 8/10 (80%) pts with Ph- B-ALL responded. The median number of cycles of INO were 3 (range, 1-6). Rates of MRD response were higher in pts without prior blinatumomab (11/13 pts [80%]), compared with those with prior blinatumomab exposure (7/14 [50%]) ( P=0.06). After a median follow-up of 21 months, 13/18 responding pts (72%) are in ongoing MRD-ve CR. Among the 18 responders, 6 pts underwent allogeneic stem cell transplant (ASCT) after a median of 3 cycles of INO (range, 1-4); all were in MRD-ve CR at the time of ASCT. 4/18 responders (22%) relapsed, 1 of whom relapsed after ASCT. Median RFS and OS for the whole group were not reached; estimated 2-year RFS and OS were 61% and 62%, respectively. 2-year OS for responders and non-responders were 76% and 50% (P=0.34), respectively. 2-year RFS for pts with or without prior blinatumomab was 23% and 91%, respectively; P=0.04. No grade 4 non-hematological toxicities were observed. 1 pt (who had a history of prior ASCT) had grade 3 sinusoidal obstruction syndrome. Conclusions: Low-dose, fractionated INO is effective at eradicating MRD in pts with B-ALL and can result in durable MRD-ve remissions. Clinical trial information: NCT03441061 . [Table: see text]
A phase II trial of palbociclib combined to letrozole after progression on second-line chemotherapy for women with ER/PR-positive high-grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer: LACOG 1018.
Authors: Fernanda Bronzon Damian, Andreia Cristina De Melo, Graziela Zibetti Dal Molin, Angelica Nogueira Rodrigues, Aknar Freire de Carvalho Calabrich, Gustavo Werutsky, Elias Abdo Filho, Taiane Francieli Rebelatto, Rafaela Gomes de Jesus, Mirela Foresti Jimenez
Journal: Journal of Clinical Oncology (2023)

5514 Background: Treatment options for patients with high-grade ovarian serous (HGSC) or endometrioid carcinoma (HGEC) who progress after receiving chemotherapy for recurrence are limited. Methods: LACOG 1018, a phase II, single-arm, multicenter trial evaluated the efficacy of letrozole 2.5mg/day po continuously plus palbociclib 125mg/day po for 21 days in 28-day cycles in patients with histologically proven ovarian HGSC or HGEC, fallopian tube or peritoneal cancer who had progressed on prior chemotherapy for locoregional recurrence or metastatic disease (at least one platinum-based regimen). Patients had centrally confirmed ER and/or PR positivity (&gt; 10% by immunohistochemistry) and ECOG PS 0-2. The primary endpoint was progression-free survival (PFS) at 12 weeks by RECIST 1.1. Secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Tumor evaluations were performed every 6 weeks until week 24. Sample size was calculated as 31 patients for the primary endpoint (90% power to detect a two-sided significance level of 5%, 45% PFS at 12 weeks) and 39 patients for secondary endpoints considering 10% drop-out. NCT03936270. Results: A total of 41 eligible patients were included in five Brazilian centers between Feb2020-Jan2022 (table). The PFS-week12 rate was 63.4% (95%CI 46.8 – 76.1). At the time of analysis (cut-off date Jan 18th, 2023) median follow-up was 18.1 months (95%CI 12.9 – 24.3), and 37 PFS events had occurred. Median PFS was 4.2 months (95%CI 2.7 – 5.5) and median OS was 13.4 months (95%CI 10.4 – 20.1). The ORR was 7.7% (N=3 PR) and the CBR was 71.8%. Treatment-related adverse event rates of any grade and grade 3-4 were 95.1 % and 51.2 %, respectively. Grade 3-4 neutropenia was reported in 17 (41.5%) patients, and febrile neutropenia in 1 (2.4%). Only one patient (2.4 %) discontinued the treatment due to toxicity. At the cut-off date, three patients remained on treatment. Conclusions: Palbociclib combined to letrozole demonstrated a significant efficacy in terms of PFS rate at 12 weeks (63.4%) and CBR (71.8%), with no new safety concerns in women with recurrent advanced and metastatic hormone receptor-positive ovarian cancer. These results warrant further investigation of palbociclib plus letrozole in high-grade ovarian cancer. Clinical trial information: NCT03936270 . [Table: see text]
Development and initial clinical testing of a multiplex assay evaluating histone modifier p300 acetylation in prostate cancer circulating tumor cells.
Authors: David Frazier Jarrard, Mikolaj Filon, Bing Yang, Jennifer L. Schehr, Anupama Singh, Marcelo Bigarella, John M Denu, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2023)

e17020 Background: Histone modifying enzymes (HMEs) hold promise as targets for drug discovery in cancer. Histone acetyltransferases and histone deacetylases dictate the presence of acetyl marks, which regulate chromatin and transcriptional activation. We previously developed a novel ‘histone array on a chip’ to measure HME dysregulation associated with the development of castration resistant prostate cancer (CRPC) (ACS Chem Biol 2017). This approach identified decreased SIRT2 expression and increased p300 activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC xenografts. These alterations were subsequently validated in castration-resistant tissues (BMC Cancer 2017). The goal of the current study was to determine if circulating tumor cells (CTCs) could be used as a therapeutic biomarker to identify patients with altered p300 acetylation activity. Methods: Blood was collected from 11 CRPC and 3 hormone-sensitive patients with advanced PC under an IRB-approved protocol. PBMCs were isolated with Ficoll-paque PLUS, and lymphocytes were depleted using anti-CD45 magnetic beads. CTCs were then captured with EpCAM labeled coated magnetic beads. Bound cells were isolated with Exclusion-based Sample Preparation (ESP) technology. Bound cells were moved through staining and washing wells prior to imaging at 20x on a fluorescent microscope. Images were analyzed with NIS Elements software. Results: We initially optimized the staining of acetyl-p300, total p300, H3K18ac, and SIRT2 in single cell prostate cancer cell cultures. Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced levels of p300 and H3K18 acetylation confirming assay specificity. CTCs from patient samples were then captured by EpCAM antibody binding and target staining revealed clear expression of acetyl-p300, acetyl-H3K18, SIRT2, and CK (cytokeratin). No expression of CD45+ cells (lymphocyte exclusion) is noted. Acetyl-p300 displayed a strong positive correlation with its target acetylated H3k18 (Pearson’s r = 0.61), and SIRT2 expression showed robust negative correlation with H3k18 (r = -0.60). A distinct group of 6/11 (55%) of CRPC patients demonstrated altered expression. In one subject with an untreated CSPC sample and subsequent CRPC sample ( &gt; 12mo) a loss of SIRT2 expression, increased p300 activity, and histone H3 hyperacetylation are associated with the transition from hormone-sensitive to CRPC. Conclusions: Acetyl-p300, H3K18ac, and SIRT2 increase in a subset of CTC from patients with CRPC. These biomarkers are associated with increased CBP/p300 activity. This biomarker suite could potentially be used for noninvasive monitoring of outcomes and predicting tumor responses to CBP/p300 acetylation inhibitors in clinical development.